In the past year, we have shifted our focus to the study of the molecular pathogenesis of human multiple myeloma (MM). We have made substantial progress on this problem, including the following findings. First, we have identified 42 genes that are selectively expressed in two MM lines compared to B lymphoblastoid lines. It is likely that some of these genes are markers of the normal plasma cell phenotype whereas others are differentially expressed as a consequence of the malignant transformation process. Second, it appears that peripheral blood B cells share clonotypic Ig gene rearrangements and mutations (and also a ras mutation in at least one instance) with the bone marrow MM tumor cell, although it remains to be determined if the clonotypic B cell is a precursor or product of the MM cell. Third, we have determined that there is selective expression of one c-myc allele in two MM cell lines that contain genetically distinct alleles despite the fact that there is no evidence of DNA rearrangement or translocation affecting the c-myc gene in either line. These results suggest that cis-dysregulation of c-myc may be a frequent occurrence in MM. Finally, we have developed a Southern blot assay to detect candidate translocations into IgH switch regions, have identified candidate translocations in all 13 MM lines examined, and have cloned 4 molecular breakpoints that involve 3 different partner chromosomes. These results support our hypothesis that translocations mediated by errors in IgH switch recombination constitute a primary oncogenic event in most MM tumors.